Agonist vs AntagonistAgonist vs Antagonist

Dr. Milton LeongDr. Milton Leong

Gonadotrophin releasing hormone analogsGonadotrophin releasing hormone analogs

GnRH analogs: GnRH-like moleculesGnRH analogs: GnRH-like molecules 2 types of GnRHa: agonists and antagonists2 types of GnRHa: agonists and antagonists

AgonistsAgonists initially enhance gonadotrophin released f initially enhance gonadotrophin released from the pituitary; but with continuing administratirom the pituitary; but with continuing administration, cause down-regulation of the pituitary and reduon, cause down-regulation of the pituitary and reduced LH & FSH secretionced LH & FSH secretion

AntagonistsAntagonists bind onto GnRH receptors and comple bind onto GnRH receptors and completely suppress the pituitary hormone secretion withitely suppress the pituitary hormone secretion within a few hoursn a few hours

Effects completely reversible after withdrawalEffects completely reversible after withdrawal

AgonistsAgonists

GnRH agonists are used in common treatment protocGnRH agonists are used in common treatment protocols:ols: Long protocol – aims at complete pituitary suppressionLong protocol – aims at complete pituitary suppression Short & ultra-short protocols – utilize the “flare-up” effectShort & ultra-short protocols – utilize the “flare-up” effect

Usage in ART treatment is well establishedUsage in ART treatment is well established Combining the use of agonists and gonadotropins in ICombining the use of agonists and gonadotropins in I

VF cycles give high pregnancy rates after IVF and ETVF cycles give high pregnancy rates after IVF and ET

Antagonists - 1Antagonists - 1

GnRH antagonists can be administered as single dose GnRH antagonists can be administered as single dose or multi dose in either a fixed or a flexible protocol or multi dose in either a fixed or a flexible protocol (O(Olivennes F et al, 2003; Mansour RT et al, 2003; Diedrich K et livennes F et al, 2003; Mansour RT et al, 2003; Diedrich K et al, 2001)al, 2001)

Usage in ART treatment is relatively newUsage in ART treatment is relatively new Advantages Advantages (Shapiro DB and Mitchell-Leef D, 2003):(Shapiro DB and Mitchell-Leef D, 2003):

shorter duration of injectable drug treatmentshorter duration of injectable drug treatment decreased gonadotropin requirement per cycledecreased gonadotropin requirement per cycle improved patient convenienceimproved patient convenience lower overall treatment costlower overall treatment cost

Antagonists - 2Antagonists - 2

Bosch E et al (Fertil & Steril Bosch E et al (Fertil & Steril 2003; 80:1444-9)2003; 80:1444-9) Prospective observational study to determine the prevalencProspective observational study to determine the prevalenc

e and the effect of premature luteinization in GnRH antagoe and the effect of premature luteinization in GnRH antago

nist IVF-ET cyclesnist IVF-ET cycles Antagonist was administered from stimulation day 6; seruAntagonist was administered from stimulation day 6; seru

m P, E2, and LH were determined on the day of hCG admim P, E2, and LH were determined on the day of hCG administrationnistration

Premature luteinization is frequent during antagonist IVF-EPremature luteinization is frequent during antagonist IVF-ET cycles and is associated with lower pregnancy and implaT cycles and is associated with lower pregnancy and implantation ratesntation rates

Progesterone elevations are not related to serum LH levels Progesterone elevations are not related to serum LH levels

Antagonists - 3Antagonists - 3

Fanchin R et al (Fertil & Steril Fanchin R et al (Fertil & Steril 2004; 81:1554-9)2004; 81:1554-9) Prospective longitudinal study to investigate Prospective longitudinal study to investigate whether premwhether prem

enstrual administration of antagonist coordinates early antrenstrual administration of antagonist coordinates early antral follicle sizes during the subsequent follicular phaseal follicle sizes during the subsequent follicular phase

On cycle day 2 (control/day 2), early antral follicles were On cycle day 2 (control/day 2), early antral follicles were measured by ultrasound, serum FSH and ovarian hormones measured by ultrasound, serum FSH and ovarian hormones were also determined; on day 25, a single 3mg cetrorelix wwere also determined; on day 25, a single 3mg cetrorelix was administered. On the subsequent day 2 (antagonist/day as administered. On the subsequent day 2 (antagonist/day 2), participants were re-evaluated as on control/day 22), participants were re-evaluated as on control/day 2

Follicular diameters and follicle-to-follicle size disparities Follicular diameters and follicle-to-follicle size disparities were decreasedwere decreased

FSH, E2, and inhibin B were lower on antagonist/day 2 thaFSH, E2, and inhibin B were lower on antagonist/day 2 than on control/day 2n on control/day 2

Antagonists - 4Antagonists - 4

Acevedo B et al (Fertil & Steril Acevedo B et al (Fertil & Steril 2004; 82:343-7)2004; 82:343-7) Randomized controlled study in donor cycles receiving eithRandomized controlled study in donor cycles receiving eith

er antagonist alone or antagonist with rLHer antagonist alone or antagonist with rLH A significant increase in MII oocyte (80% vs. 71%), fertilizA significant increase in MII oocyte (80% vs. 71%), fertiliz

ation rates (83% vs. 71%), G1 embryos (17% vs. 3%), and ation rates (83% vs. 71%), G1 embryos (17% vs. 3%), and implantation rates (35% vs. 15%) in recipients whose embrimplantation rates (35% vs. 15%) in recipients whose embryos originated from donors receiving antagonist + rLH as cyos originated from donors receiving antagonist + rLH as compared to donors receiving antagonist aloneompared to donors receiving antagonist alone

E2 levels, pregnancy/transfer and clinical pregnancies were E2 levels, pregnancy/transfer and clinical pregnancies were lower (not significant) in donors treated with antagonist alolower (not significant) in donors treated with antagonist alone vs. those receiving the rLH-supplemented antagonistne vs. those receiving the rLH-supplemented antagonist

Controlled Studies on Agonist vs Antagonist - 1Controlled Studies on Agonist vs Antagonist - 1

Akman MA et al (Hum Reprod 2001, 16(5):868-70)Akman MA et al (Hum Reprod 2001, 16(5):868-70) Prospective randomized trial on poor responders:Prospective randomized trial on poor responders:

group 1 – agonistic flare-up protocolgroup 1 – agonistic flare-up protocol

group 2 – antagonistic multi-dose protocolgroup 2 – antagonistic multi-dose protocol E2 levels on the day of hCG were lower in group 2 compareE2 levels on the day of hCG were lower in group 2 compare

d with group 1d with group 1 Clinical pregnancy and implantation rates did not show any Clinical pregnancy and implantation rates did not show any

significant differencesignificant difference Limitation of this study: small sample size, with only 24 subLimitation of this study: small sample size, with only 24 sub

jects in each groupjects in each group

Controlled Studies on Agonist vs Antagonist - 2Controlled Studies on Agonist vs Antagonist - 2 Vlaisavljevic V et al (Reprod Biomed Online 2003, 7Vlaisavljevic V et al (Reprod Biomed Online 2003, 7

(3):301-8)(3):301-8) Prospective randomized study:Prospective randomized study:

group 1 – single dose long agonist (goserelin) protocolgroup 1 – single dose long agonist (goserelin) protocolgroup 2 – single 3mg dose antagonist (cetrorelix) protocol, group 2 – single 3mg dose antagonist (cetrorelix) protocol, when the mean follicle diameter exceeded 12mmwhen the mean follicle diameter exceeded 12mm

The mean number of ampoules of FSH and the duration of stThe mean number of ampoules of FSH and the duration of stimulation were statistically significantly lower in group 2 thimulation were statistically significantly lower in group 2 than in group 1an in group 1 (25.9 versus 34.5, and 9.6 versus 12.2 days, P < 0.01) (25.9 versus 34.5, and 9.6 versus 12.2 days, P < 0.01)

The mean number of oocytes retrieved, fertilization rates, blThe mean number of oocytes retrieved, fertilization rates, blastulation rates and blastocyst transfer rates were similar in astulation rates and blastocyst transfer rates were similar in both groupsboth groups

Clinical pregnancy and delivery rates per cycle were higher iClinical pregnancy and delivery rates per cycle were higher in group 1n group 1 (34.3 and 30.1%) (34.3 and 30.1%) than in group 2than in group 2 (31.9 and 28.3%), (31.9 and 28.3%), but but the differences were not statistically significantthe differences were not statistically significant

Controlled Studies on Agonist vs Antagonist - 3Controlled Studies on Agonist vs Antagonist - 3

Loutradis D. et al (Fertil & Steril 2004, 82(5):1446-8)Loutradis D. et al (Fertil & Steril 2004, 82(5):1446-8) Prospective randomized study:Prospective randomized study:

group A – long protocol of agonistgroup A – long protocol of agonist

group B – modified multi-dose antagonist protocol, starting group B – modified multi-dose antagonist protocol, starting when the largest follicle had reached 14mm, with simultanewhen the largest follicle had reached 14mm, with simultaneous augmentation of 75IU rFSH up to and including the day ous augmentation of 75IU rFSH up to and including the day of hCG administrationof hCG administration

No improved pregnancy and implantation ratesNo improved pregnancy and implantation rates

Meta-analysis on Agonist vs Antagonist - 1Meta-analysis on Agonist vs Antagonist - 1

Ludwig M, Katalinic A, Diedrich K (Arch Gynecol OLudwig M, Katalinic A, Diedrich K (Arch Gynecol Obstet 2001; 265(4):175-82)bstet 2001; 265(4):175-82) A meta-analysis performed to evaluate whether there is a reA meta-analysis performed to evaluate whether there is a re

duction in cases of severe OHSS and/or a reduction in pregduction in cases of severe OHSS and/or a reduction in pregnancy rates when using antagonistsnancy rates when using antagonists

Cetrorelix but not ganirelix will reduce the incidence of casCetrorelix but not ganirelix will reduce the incidence of cases of OHSSes of OHSS

Cetrorelix but not ganirelix will result in the same pregnancCetrorelix but not ganirelix will result in the same pregnancy rates as the long agonist protocoly rates as the long agonist protocol

Meta-analysis on Agonist vs Antagonist - 2Meta-analysis on Agonist vs Antagonist - 2

Al-Inany H and Aboulghar M (Hum Reprod 2002; 17:Al-Inany H and Aboulghar M (Hum Reprod 2002; 17:874-85)874-85) A Cochrane reviewA Cochrane review 5 randomized trials were included, comparing fixed protoc5 randomized trials were included, comparing fixed protoc

ol of antagonist with long protocol of GnRH agonistol of antagonist with long protocol of GnRH agonist The clinical pregnancy rate was lower using antagonistThe clinical pregnancy rate was lower using antagonist No significant difference in prevention of premature LH suNo significant difference in prevention of premature LH su

rge and prevention of severe OHSSrge and prevention of severe OHSS